Gastric acid secretion inhibiting composition

ABSTRACT

An oral pharmaceutical dosage form comprises pharmacologically effective amounts of an acid susceptible proton pump inhibitor or a salt thereof, an H2 receptor antagonist or a salt thereof and a pharmaceutically acceptable carrier. The dosage form is capable of raising gastric pH to above 4 within two hours after administration and to keep it at that level for at least 4 hours. Also disclosed is a method of manufacture of the dosage form, its use in treating dyspepsia and infection by  Helicobacter pylori , and a method of treating disorders associated with gastric acid secretion.

FIELD OF THE INVENTION

[0001] The present invention relates to a gastric acid secretioninhibiting composition, to a method for its manufacture and to its usein treating conditions which are related to the secretion of gastricacid.

BACKGROUND OF THE INVENTION

[0002] Dyspepsia (acid dyspepsia) is a common disorder. Heartburn is asymptom of dyspepsia. It is estimated that 44% of Americans haveheartburn at least once monthly but that only about 25% of them areseeing the doctor because of their dyspepsia problem. Symptomsassociated with dyspepsia are for instance upper abdominalpain/discomfort and heartburn, indigestion, “sour” stomach, andgastro-esophageal reflux.

[0003] Dyspepsia is a multi-factorial disease and may be associated withorganic pathology such as duodenal ulcer, gastric ulcer, esophagitis,Barrett's esophagus or gastro-duodenal inflammation (e.g., Helicobacterpylori infection). Dyspepsia also includes conditions where no organicpathology can be found, e.g., non-ulcer dyspepsia (NUD) or functionaldyspepsia.

[0004] Dyspepsia can be controlled by administration of medicines thatreduce the pH in the stomach. Therapeutic agents effective in thetreatment of dyspepsia include gastric acid suppressing agents, such ashistamine H2 receptor antagonists (in the following called H2 receptorantagonists), acid susceptible proton pump inhibitors,antacids/alginates, anticholinergics and prokinetic agents. They can bedistinguished by their mechanism of action, safety profile, andpharmacokinetics. The stomach pathogen Helicobacter pylori has beenassociated with dyspepsia, gastro-duodenal ulcer disease and stomachcancer. The treatment of H. pylori infection usually comprises theadministration of a combination of acid secretion suppressing agents andone or two antibiotic agents.

[0005] The therapeutic effect on dyspepsia related discomfort andorganic lesions when inhibiting acid production by administration ofacid secretion-inhibiting drugs is related to the degree of acidinhibition as well as to the onset and duration of action of theparticular drug. The majority of patients who have symptomatic acidreflux disease have a normal esophageal mucosa or only a mild degree ofesophagitis. Treatment to relieve symptoms as they occur may be the bestway to manage these patients, to whom the speed of symptom relief is ofprimary importance.

[0006] Antacid agents, that is, acid neutralizing agents, and alginatesare the first therapeutic choice in the treatment of mild heartburn.They have a extremely short duration of action but are seen asinexpensive and safe. Antacid agents work locally through aneutralization of gastric acid. Alginates provide some mechanicalprotection against reflux of gastric acid into the esophagus. The mainadvantages of antacid agents and alginates are, that they provide fastrelief of symptoms. The main disadvantage of antacid agents andalginates is the extremely short duration of action and dosing has to berepeated frequently to keep the patients free of symptoms, further thatantacids often do not provide symptom resolution, i.e. complete reliefof symptoms.

[0007] Several classes of compounds are known which affect the secretionof gastric acid. Among them proton pump inhibitors, such as thesubstituted benzimidazoles omeprazole, lansoprazole, rabeprazole,pantoprazole, and H2 receptor antagonists, such as cimetidine,ranitidine, famotidine, are the most prominent ones. H2 receptorantagonists and acid susceptible proton pump inhibitors are widelyprescribed for reducing gastric acid secretion systemically. After 5days' treatment, acid susceptible proton pump inhibitors have inclinical studies been proven to be very effective in providing symptomresolution in patients with dyspepsia associated with gastric ulcers,duodenal ulcers, reflux esophagitis and gastro-esophageal reflux withoutesophagitis. Acid susceptible proton pump inhibitors and H2 receptorantagonists, respectively, have also proven to be effective in curing H.pylori infection in combination with one or two antibiotics(Gschwandtler M et al., Aliment Pharmacol Ther 1999, 13(8):1063-9). Itis established that omeprazole is superior to H2 receptor antagonistsregarding healing of gastro-duodenal and esophageal lesions as well asproviding dyspeptic symptom resolution in these conditions (Eriksson S.,European Journal of Gastroenterology & Hepatology 1995, 7:465).

[0008] Various combinations of antacid and/or mucosa protecting agentswith agents that reduce acid secretion have been disclosed to be usefulin treating dyspepsia.

[0009] WO 95/017080 describes a composition for use in the treatment offor instance heartburn comprising an H2 receptor antagonist, such asfamotidine, and an alginate and optionally simethicone (an activatedpolysiloxane).

[0010] EP 338861 A describes a solid pharmaceutical preparationconsisting of an antacid and excipients which is proposed to be used incombination with an acid susceptible proton pump inhibitor or any othersubstance inhibiting gastric acid secretion. There is no suggestion tocombine these substances in a fixed unit dosage form.

[0011] U.S. Pat. No. 5,244,670 A describes an ingestible pharmaceuticalcomposition comprising a substance selected from the group consisting ofantacid agents, acid secretion prevention agents, bismuth-containingagents and their mixtures, and 3-(1-menthoxy)-propane-1,2-diol which ispresent to provide a cooling sensation to the throat.

[0012] WO 97/25066 discloses a pharmaceutical formulation comprising acombination of an acid susceptible proton pump inhibitor or an H2receptor antagonist and one or more antacid agents or alginates.

[0013] Neither acid susceptible proton pump inhibitors nor H2 receptorantagonists, alone or in combination with antacids and/or alginates,provide fully satisfactory quick and lasting relief to patients, to whomthe speed of symptom relief is of primary importance but who also desireto be free of symptoms for a longer period of time.

OBJECTS OF THE INVENTION

[0014] It is an object of the invention to provide a medicine whichprovides quick and lasting relief to a patient suffering from conditionsrelated to gastric acid secretion.

[0015] It is another object of the invention to provide a method fortreating a patient suffering from conditions related to gastric acidsecretion which provides quick and lasting relief.

[0016] Further objects of the invention will be evident from thefollowing short description of the invention, a preferred embodimentthereof, and the appended claims.

SUMMARY OF THE INVENTION

[0017] The present invention is based on the insight that acidsusceptible proton pump inhibitors and H2 receptor antagonists possessmutually supplementing properties in respect of inhibiting acidsecretion and that they can be used for designing a pharmaceuticalcomposition which provides quick and lasting relief to a patientsuffering from conditions related to gastric acid secretion.

[0018] Acid susceptible proton pump inhibitors are acid activatedprodrugs that covalently inhibit the gastric H+,K+-ATPase, theproton-transporting enzyme involved in the production of hydrochloricacid in the stomach. The action of gastric H+,K+-ATPase represents thefinal step in the sequence of events resulting in secretion ofhydrochloric acid by the parietal cell. Thus inhibition of this enzymeis the most effective and specific means of controlling acid secretionregardless of the nature of the stimulus to secretion. As would beexpected with such a mechanism of action, omeprazole has been shown toinhibit both basal and stimulated acid secretion. Omeprazole is a weakbase which accumulates in the acidic milieu of the secretory membrane ofthe parietal cell where it undergoes rearrangement in acid to its activesulphenamide form which subsequently reacts with sulfhydryl groups ofthe acid pump.

[0019] In gastric mucosa, the acid susceptible proton pump is situatedin the apical membrane and in the tubovesicles bordering the secretorycanaliculi of the parietal cell. Thus, after a single dose, omeprazolerapidly accumulates in the acidic compartment of the secretory membranewhere its active sulphenamide form irreversible binds to theH+,K+-ATPase. The H+,K+-ATPase situated in the tubovesicles will howevernot be exposed for activated omeprazole. A major portion of synthesizedH+,K+-ATPase will thus escape blockade after a single omeprazole dose.This may explain why the maximal acid inhibitory effect of omeprazole isreached only after about five days treatment.

[0020] H2 receptor antagonists competitively inhibit the action ofhistamine on all H2 receptors, mainly on the surface of the parietalcells. At therapeutic doses these agents are capable not only ofdecreasing both basal and nocturnal acid secretion, but also secretionstimulated by food, histamine, insulin and pentagastrin. A single doseof an H2 receptor antagonist results in maximal acid inhibitory effectalready within 2 hours after intake. Furthermore, the acid inhibitoryeffect obtained with high doses of an H2 receptor antagonist is built uprapidly but has a tendency to fade substantially during the following2-7 days, while the acid inhibitory effect of omeprazole gradually isbuilt up during the same period of time.

[0021] According to the invention, by combining an H2-receptorantagonist with an acid susceptible proton pump inhibitor, it ispossible to obtain rapid onset of action as well as good long-termefficacy.

[0022] Thus, according to the invention, is provided an oralpharmaceutical dosage form comprising pharmacologically effectiveamounts of an acid susceptible proton pump inhibitor or a salt thereof,and an H2 receptor antagonist or a salt thereof, and a pharmaceuticallyacceptable carrier. The terms “proton pump inhibitor” and “H2 receptorantagonist” include their isomers, such as enantiomers of proton pumpinhibitors, as well as pharmaceutically acceptable salts of suchisomers.

[0023] The invention is especially suitable for “on demand” treatment ofgastro-esophageal reflux complaints e.g. heartburn, where potent acidreduction is needed for a shorter period of time and where a rapid onsetof action is most important and a maximal acid reduction is to prefer.The maximal acid inhibitory effect would be able to be maintained duringa 7 days period by the elimination of the “fade-off” phenomenon seenafter H2-blocker given alone. This will be important in order to reducethe time for the treatment of stomach ulcers, acid related lesions inthe esophagus and Helicobacter pylori eradication.

[0024] According to the invention is provided an oral dosage formcomprising an H2 receptor antagonist in an amount effective to reducethe acidity in the stomach after administration and an acid susceptibleproton pump inhibitor in an amount effective to sustain the low acidityeffected by the H2 receptor antagonist over an extended period of time.It is preferred for the pharmacologically effective amounts to beamounts capable of raising gastric pH to above 3 within 2 hours fromadministration and to keep it above 3 for at least 4 hours, preferablyfor at least 8 hours. It is more preferred for said pharmacologicallyeffective amounts to be amounts capable of raising gastric pH to above 4within two hours after administration and to keep it above 4 for atleast 4 hours, more preferred for at least 8 hours.

[0025] According to a first preferred aspect of the invention the H2receptor antagonist is provided in an amount which is capable ofproviding at least 80% of maximal reduction, more preferred at least 95%of maximal reduction, of the acidity in the stomach within about twohours. “Maximal reduction” is the reduction of acidity which can bemaximally obtained by administering an H2 receptor antagonist alone intherapeutically accepted amounts, that is, in amounts in which suchdrugs are administered in the art. The term “H2 receptor antagonist(s)”as used herein includes all agents that substantially inhibit or blockthe secretion of gastric acid by binding to a histamine receptor in thestomach. At therapeutic doses such H2 receptor antagonists are capablenot only of decreasing basal and nocturnal acid secretion, but alsosecretion stimulated by food, histamine, insulin and pentagastrin.Exemplary H2 receptor antagonists according to the invention arecimetidine, ranitidine, nizatidine and famotidine which are normallyused in form of their pharmacologically acceptable salts, in particularhydrochlorides. The dosage form of the invention preferably comprisesfrom 1 mg to 800 mg of H2 receptor antagonist or salt thereof, morepreferred from 5 mg to 400 mg.

[0026] According to a second preferred aspect of the invention the acidsusceptible proton inhibitor is provided in an amount which is capableof maintaining the low acidity effected by the histamine H2 antagonistover at least 6 hours. Acid susceptible proton pump inhibitors arerapidly taking market share from H2 receptor antagonists. The term “acidsusceptible proton pump inhibitor(s)”, as used herein, comprisesbenzimidazole derivatives having substantial H+,K+-ATPase inhibitingactivity, in particular omeprazole, pantoprazole, lanzoprazole,rabeprazole, pariprazole, leminoprazole and their pharmaceuticallyacceptable salts and enantiomers and salts of enantiomers, but includealso the other compounds disclosed on pages 7-11 of WO 97/25066 whichare hereby incorporated by reference as well as those disclosed in EP005 129 A1, EP 174 726 A1, EP 166 287 A1, GB 2 163 747, WO 90/06925,WO91/19711, WO91/19712, WO94/27988, WO95/01977. Omeprazole is known tooffer significant gain over H2 receptor antagonists in terms of symptomresolution, healing and prevention of relapse. 3.

[0027] Thus the dosage form of the invention comprises preferably from 1mg to 100 mg, more preferred from 5 mg to 50 mg, per single dose of anacid susceptible proton pump inhibitor or a salt thereof. Preferably theacid susceptible proton pump inhibitor or salt thereof is separated fromthe H2 receptor antagonist by an enteric coating.

[0028] According to a fourth preferred aspect of the invention the H2receptor antagonist and the acid susceptible proton pump inhibitor neednot to be comprised by the same pharmaceutical composition but may beadministered separately but within a narrow time interval, such as atime interval of one hour, in particular a time interval of 30 min, mostpreferred a time interval of 10 min. Thus is disclosed a correspondingdose regimen for separate but joint administration of an acidsusceptible proton pump inhibitor and an H2 receptor antagonist to treata condition related to gastric acid secretion.

[0029] The oral dosage form of the invention thus comprises an acidsusceptible proton pump inhibitor, an H2 receptor antagonist and apharmaceutical carrier and, optionally, a gastric acid suppressing agentand/or an alginate. Preferably, the dosage form of the inventioncomprises from 100 mg to 1000 mg of antacid agent and/or alginate. Theantacid agent of the invention comprises one or several of aluminumhydroxide, calcium carbonate, magnesium carbonate, basic magnesiumcarbonate, magnesium hydroxide, magnesium oxide, sodium hydrogencarbonate.

[0030] According to a fifth preferred aspect of the invention thebioavailability of the acid susceptible proton pump inhibitor isimproved for the first three consecutive doses of a dose regimen orcomposition of the invention in the treatment of dyspepsia, inparticular the first five consecutive doses, since less proton pumpinhibitor will be degraded during passage of the drug through thestomach.

[0031] Due to the fact that acid susceptible proton pump inhibitors aregenerally sensitive to acid (acid susceptible proton pump inhibitors)they need to be administered in a form which protects them fromdegradation in the stomach to make them pass into the small intestinewhere they-are absorbed. H2 receptor antagonists, on the other hand, canbe administered without such protection. According to a furtherpreferred aspect of the invention, compositions can be adapted to suitthe purpose of the present invention are among those disclosed in WO97/25066.

[0032] The oral dosage forms of WO 97/25066 comprise an acid susceptibleproton pump inhibitor in an amount similar or identical to that used inthe composition of the present invention, and one or several antacidagents and/or alginate(s). The adaptation of the compositions of WO97/25066 essentially consists in substituting a pharmacologicallyeffective amount of an H2 receptor antagonist for a portion of or theentire amount of the antacid agent(s) and/or alginate.

[0033] According to the invention is provided an oral, multiple unittableted dosage form comprising an acid susceptible proton pumpinhibitor in individually enteric coating layered units in combinationwith an H2 receptor antagonist in the form of a powder or granulescompressed into a tablet. The enteric coating layer(s) covering theindividual units of the acid susceptible proton pump inhibitor hasproperties such that the compression of the units into a tablet does notsignificantly affect the acid resistance of the individually entericcoating layered units. Furthermore, the multiple unit tableted dosageform provides a good stability to the active substances during long-termstorage.

[0034] According to the invention is also provided a multiple unittableted dosage form, which is divisible and easy to handle. Such amultiple unit tableted dosage form comprises enteric coating layeredpellets of an acid susceptible proton pump inhibitor compacted with apulverous H2-antagonist. This dosage form may also contain effervescentcomponents for making it rapidly disintegrate when put into water; thepH of the aqueous phase thereby must be made slightly acidic to preventdissolution of the enteric layer. This dosage for can be given topatients with swallowing disorders and in pediatrics. Such a suspensionof dispersed units/pellets of appropriate size can be used for oraladministration and also for feeding through a naso-gastric tube.

[0035] According to the invention is also provided a tablet preparationcomprising an acid susceptible proton pump inhibitor in admixture withtablet excipients forming a tablet core which is enterically coated, anda separate layer surrounding the tablet core. The surrounding layercomprises an H2 receptor antagonist in admixture with a pharmaceuticalcarrier. Optionally a separating layer is applied on the tablet corebefore the core is enteric coating layered. Alternatively, the preparedtablet is sectioned in separate layers, each one comprising differentactive substances. One of the layers, preferably the innermost layer(core), comprises the acid susceptible proton pump inhibitor in the formof enteric coating layered pellets in admixture with pharmaceuticalexcipients and the other layer(s) comprise(s) the histamineH2-antagonist(s), respectively in admixture with pharmaceuticalexcipient(s). Optionally the two layers are separated by a separatinglayer to prevent tacking between the two layers. The core comprising theacid susceptible proton pump inhibitor may also be advantageously coateddirectly with an enteric layer by following, for instance, proceduresdisclosed in WO 00/78284 which is incorporated herein by reference.

[0036] According to the invention the acid susceptible proton pumpinhibitor in the form of enteric coating layered pellets may be mixedwith histamine H2-antagonist(s) and optionally pharmaceuticalexcipient(s) to be administered in a sachet intended for oraladministration after dispersion in a slightly acidic aqueous solution.

[0037] It is thus preferred for the dosage form of the invention tocomprise the acid susceptible proton pump inhibitor or a salt thereofprotected by an enteric coating layer and, optionally, a layerseparating it from the enteric coating. Preferably the dosage form ofthe invention comprises two concentric layers optionally separated byone or more separating layer(s), one layer comprising said acidsusceptible proton pump inhibitor or salt thereof, the other layercomprising said H2 receptor antagonist or salt thereof. The inner layercomprises the acid susceptible proton pump inhibitor or salt thereof andthe outer layer comprises the H2 receptor antagonist or salt thereof.According to the invention it is also possible for the outer layer tocomprise the acid susceptible proton pump inhibitor or salt thereof andfort the inner layer to comprise the H2 receptor antagonist or saltthereof. According to a preferred aspect the inner layer comprises adisintegrant. The oral dosage form of the invention may take differentshapes, such as a tablet, a capsule, a divided powder/pelletformulation, and the like.

[0038] According to the invention is also disclosed a method for themanufacture of an oral tableted dosage form comprising amounts of anacid susceptible proton pump inhibitor or salt thereof and an H2receptor antagonist or salt thereof pharmacologically effective intreating a condition related to dyspepsia, the method comprising forminga first layer comprising said acid susceptible proton pump inhibitor orsalt thereof, an enteric coat surrounding said first layer, and a secondlayer comprising said H2 receptor antagonist or salt thereof surroundingsaid first layer and said enteric coat. Also disclosed is a method forthe manufacture of an oral dosage form comprising amounts of an acidsusceptible proton pump inhibitor or salt thereof and an H2 receptorantagonist or salt thereof pharmacologically effective in treating acondition related to dyspepsia, the method comprising forming pelletscomprising said acid susceptible proton pump inhibitor or salt thereof,covering said pellets with enteric coat, and mixing said pellets coveredwith said enteric coat with a carrier comprising said H2 receptorantagonist or salt thereof; the carrier may comprise a disintegrant. Theaforementioned methods of the invention further comprise a final tabletforming step, possibly followed by a film-covering step.

[0039] Another method for the manufacture of the oral dosage form of theinvention comprises filling a capsule capable of disintegrating ingastrointestinal fluids to release its contents with the mixturecomprising enteric proton pump inhibitor pellets and a H2 receptorantagonist in powderous or granular form.

[0040] A further method for the manufacture of the oral dosage form ofthe invention comprises forming a layer comprising an acid susceptibleproton pump inhibitor or salt thereof and an H2 receptor antagonist orsalt thereof, and covering said layer with an enteric coat.

[0041] A still further method for the manufacture of the oral dosageform of the invention comprises forming a mixture comprising an acidsusceptible proton pump inhibitor or salt thereof and an H2 receptorantagonist or salt thereof, filling the mixture in a capsule capable ofdisintegrating in gastrointestinal fluids to release its contents, andcovering the capsule with an enteric coat.

[0042] The use of the pharmaceutical dosage form of the invention ishowever not restricted to provide quick and lasting relief to a patientsuffering from conditions related to gastric acid secretion. The rapidonset of inhibition of gastric acid secretion combined with themaintenance of inhibition as long as desired (by repeated administrationof a composition comprising an acid susceptible proton pump inhibitor,preferably by repeated administration of the composition of theinvention) can be expected to have a positive effect on the healing ofesophagitis for which the maintenance of intra-gastric pH above 4 for amaximal duration is acknowledged (Huang J Q and Hunt R H, pH, healingrate and symptom relief in patients with GERD, Yale J Biol Med 1999,72:181-94). The composition of the invention thus is also preferred formaintaining gastric pH above 4 for extended periods of time, such as 4hours and more.

[0043] According to the invention the aforementioned mixture comprisingan acid susceptible proton pump inhibitor or salt thereof and an H2receptor antagonist or salt thereof can be used for the manufacture of amedicament for the treatment of a disorder associated with gastric acidsecretion.

[0044] The dosage form of the invention can also be used, in associationwith one or more antibiotic agent(s), for the eradication ofHelicobacter pylori.

[0045] According to the invention is also disclosed a method of treatingdisorders associated with gastric acid secretion, the method comprisingthe administration of the dosage form of the invention or theconcomitant administration of two separate oral dosage forms, onecomprising a pharmacologically effective amount of an acid susceptibleproton pump inhibitor or salt thereof, the other comprising apharmacologically effective amount of an H2 receptor antagonist or saltthereof.

[0046] Furthermore, according to the invention is disclosed a method oftreating an infection by Helicobacter pylori, comprising theadministration of the dosage form of the invention or the concomitantadministration of two separate oral dosage forms, one comprising apharmacologically effective amount of an acid susceptible protoninhibitor or salt thereof, the other comprising a pharmacologicallyeffective amount of an H2 receptor antagonist or salt thereof, inassociation with the administration of one or more antibiotic agent(s)effective against H. pylori.

[0047] It is preferred for the aforementioned methods of treatmentaccording to the invention to comprise a dose regimen capable ofmaintaining gastric pH above 4 for at least 95% of the time periodstarting at 2 hours from the administration of the first dose andextending until 6 hours from the administration of the last dose, inparticular a regiment wherein the time period is one week or more,preferably two weeks or more, even more preferred four weeks or more.Also preferred in this context is a dose regimen capable of maintaininggastric pH above 3 for at least 95% of the time period starting at 2hours from the administration of the first dose and extending until 6hours from the administration of the last dose, in particular for fourweeks or more.

[0048] The invention will now be described in greater detail byreference to a number of preferred but not limiting embodimentsillustrated in a drawing.

BRIEF DESCRIPTION OF THE FIGURES

[0049] FIGS. 1-6 are schematic cross sections illustrating:

[0050]FIG. 1 a multiple unit tableted dosage form comprising an acidsusceptible proton pump inhibitor in the form of enteric coating layeredpellets in admixture with an H2-receptor antagonist dispersed in apharmaceutical carrier;

[0051]FIG. 2 a tableted dosage form consisting of two halves, one ofwhich comprises enteric coating layered pellets of an acid susceptibleproton pump inhibitor in admixture with excipients whereas the othercomprises an H2 receptor antagonist in admixture with excipients;

[0052]FIG. 3 a multiple-layered tableted dosage form comprising an acidsusceptible proton pump inhibitor in a core surrounded by an entericcoating layer and a layer containing an H2 receptor antagonist dispersedin a pharmaceutical carrier surrounding the core;

[0053]FIG. 4 a tableted dosage form comprising an acid susceptibleproton pump inhibitor, an H2-receptor antagonist and excipients inadmixture, provided with an enteric coating;

[0054]FIG. 5 a capsule dosage form containing an acid susceptible protonpump inhibitor in enteric coating layered pellets in admixture with anH2 receptor antagonist and pharmaceutical excipients;

[0055]FIG. 6 an acid resistant capsule dosage form containing an acidsusceptible proton pump inhibitor, an H2 receptor antagonist andexcipients;

[0056]FIG. 7 is a diagram of the gastric pH trace in a person afteradministration of a conventional omeprazole oral dosage form;

[0057]FIG. 8 is a diagram of the gastric pH trace in the same personafter joint administration of omeprazole and famotidine according to theinvention.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0058] Multiple unit tableted dosage form. The multiple unit tableteddosage form of the invention illustrated in FIG. 1 consists of a tabletbody 1 optionally covered by a film layer 3 and small pellets 2distributed at random in the tablet body 2. The pellets 2 contain anacid susceptible proton pump inhibitor in form of the racemate, analkaline salt or one of its enantiomers. The individually entericcoating layered units 2 (small beads, granules or pellets) containingthe acid susceptible proton pump inhibitor and optionally containingalkaline substances, are mixed with the H2 receptor antagonist andconventional tablet excipients forming, in combination, the tablet body1. The H2 receptor antagonist and tablet excipients may be dry mixed orwet mixed into granules. The mixture of enteric coated layered units, H2receptor antagonist and excipients are compressed into the multiple unittableted dosage forms. By the expression “individual units” is meantsmall beads, granules or pellets, in the following referred to as protonpump inhibitor pellets. In compressing the mixture into tablets, caremust be taken not to significantly affect the acid resistance of theenteric coated layered pellets. In regard of the core material forenteric coating layered pellets comprising an acid susceptible protonpump inhibitor reference is made to WO 97/25066, page 13, next but lastparagraph, to page 15, end of second paragraph, which are herebyincorporated by reference. In regard of the enteric coating layer(s)reference is made to WO 97/25066, page 15, next but last paragraph, topage 18, end of second paragraph, which are hereby incorporated byreference. The acid susceptible proton pump inhibitor pellets coveredwith enteric coating layer(s) may be further covered with one or moreover-coating layers. In regard of such over-coating layer(s) referenceis made to WO 97/25066, page 18, last paragraph, to page 19, end offirst paragraph, which are hereby incorporated by reference. The H2receptor antagonist is dry mixed with inactive excipients such asfiller, binders, disintegrants, and other pharmaceutically acceptableadditives. The mixture is wet massed with a granulation liquid. The wetmass is dried preferably to a loss on drying of less than 3% by weight.Then the dry mass is milled to a suitable size for granules, preferablysmaller than 1 mm. Suitable inactive excipients are, for instance,mannitol, corn starch, potato starch, low substituted hydroxypropylcellulose, microcrystalline cellulose and crosslinkedpolyvinylpyrrolidone. The dry mixture comprising the H2 receptorantagonist may be mixed with a suitable granulation liquid comprising,for instance, hydroxypropylcellulose or polyvinylpyrrolidone dissolvedin water or alcohol or their mixtures. Alternatively the H2 receptorantagonist is dry mixed with pharmaceutically acceptable excipients (seesupra).

[0059] Multi unit tablets. The enteric coated layered pellets comprisingan acid susceptible proton pump inhibitor are mixed with the H2 receptorantagonist granules or with the prepared dry mixture comprising the H2receptor antagonist. The mixture is admixed with lubricant(s) andcompressed into a multiple unit tableted dosage form. Suitablelubricants for the tableting process are, for instance, sodium stearylfumarate, magnesium stearate and talc. The compressed tablets areoptionally covered with filmforming agent(s) to obtain a smooth surface.Such coating layer may further comprise additives such as anti-tackingagents, colorants and pigments or other additives.

[0060] The fraction of enteric coating layered pellets constitutespreferably less than 60% by weight of the total tablet weight. Thepreferred multiple unit table formulation thus consists of entericcoated layered pellets comprising the acid susceptible proton pumpinhibitor, optionally in admixture with alkaline reacting compound(s),compressed into tablets with the prepared H2 receptorantagonist/excipient(s) mixture. The enteric coating layer(s) make(s)the pellets of the dosage form insoluble in acidic media butdisintegrating/dissolving in near neutral to alkaline media such as, forinstance, the gastric fluid present in the proximal part of the smallintestine where the dissolution and uptake of the acid susceptibleproton pump inhibitor is desired. The enteric coating layered protonpump inhibitor pellets may also be covered with an overcoating layerbefore being formulated into tablets, and they may also contain one ormore separating layer(s) in between the core material and the entericcoating layer(s).

[0061] Process for making multi-unit tablets. The process for themanufacture of the dosage form represents a further aspect of theinvention. After formulating the pellets by dry mixing (orderedmixture), spray coating or layering of the acid susceptible proton pumpinhibitor onto seeds, or by extrusion/spheronization or granulation, thepellets are first optionally covered with the separating layer(s) andthen with the enteric coating layer(s), or a separating layer isspontaneously developed in situ between the core material and theenteric coating layer material. The coating is carried out as describedabove and in the accompanying examples. The preparation of the H2receptor antagonist mixture is also described in the examples.

[0062] The enteric coating layered pellets, with or without an overcoat,are mixed with the prepared H2 receptor antagonist granules or drypowder, tablet excipients and other pharmaceutically acceptableadditives and compressed into tablets. Alternatively, the enteric coatedproton pump inhibitor pellets may be covered by a second layercontaining the H2 receptor antagonist as described in the followingexamples. Furthermore, as illustrated in FIG. 2, the enteric coatinglayered pellets 4 may be intimately mixed with excipients 5 andprecompressed and further layered with the H2 receptor antagonistpreparation 7 and finally compressed into a tablet, optionally withfilm-forming agent(s) 6 to obtain a smooth surface. As a furtheralternative illustrated in FIG. 3 the acid susceptible proton pumpinhibitor in form of a powder may be mixed with tablet excipients andcompressed into a tablet 8 which is optionally layered with a separatinglayer and thereafter enteric coating 9 layered. The thus produced tabletcore is presscoated with the H2 receptor antagonist preparation 10.Finally the table may be covered with a tablet coat 11 to obtain asmooth surface.

[0063] It is also possible to fill the acid susceptible proton pumpinhibitor in form of enteric coated layered pellets in a sachet togetherwith H2 receptor antagonist optionally mixed with excipients.

[0064]FIG. 4 illustrated a tableted dosage form with a core 12comprising an acid susceptible proton pump inhibitor and an H2 receptorantagonist dispersed in a pharmaceutical carrier, the core 12 beingsurrounded by an enteric coat 13.

[0065]FIG. 5 illustrates a hard gelatin capsule 16 filled with theuncompressed core material 14, 15 of the embodiment of FIG. 1.

[0066]FIG. 6 illustrates a hard gelatin capsule 18 comprising an entericcoat filled with the uncompressed core material 17 of the embodiment ofFIG. 4.

[0067] In general, the methods of WO 97/25066 for making oralpharmaceutical dosage forms comprising an acid susceptible proton pumpinhibitor and an antacid agent or alginate can be adapted to suit thepurpose of the invention by substituting part or the entire amount ofantacid agent or alginate by a pharmacologically effective amount of anH2 receptor antagonist, the remainder of the antacid agent or alginate(if substitution is not 1:1 by weight) being omitted or substituted byexcipients like microcrystalline cellulose, silica, lactose, mannitol,ant the like.

[0068] Use of the Dosage Forms According to the Invention.

[0069] The dosage forms according to the invention are especiallyadvantageous in the treatment of dyspepsia and other gastrointestinaldisorders related to the production of gastric acid to provide quick andlasting relief from symptoms. The dosage forms are administered once orseveral times a day. The typical daily dose of the acid susceptibleproton pump inhibitor and the H2 receptor antagonist will depend onvarious factors such as individual requirements of patients, the mode ofadministration, and the particular condition to be treated. In generaleach dosage form will comprise from 1 mg to 100 mg of acid susceptibleproton pump inhibitor and from 1 to 800 mg of the H2 receptorantagonist. Preferably each dosage form will comprise from 5 to 50 mg ofthe acid susceptible proton pump inhibitor and from 5 to 200 mg of theH2 receptor antagonist. The multiple unit tablet preparation is alsosuitable for dispersion in water which had been made slightly acidic bythe addition of citric acid.

EXAMPLE 1

[0070] Multiple unit tableted dosage form comprising magnesiumomeprazole and ranitidine hydrochloride; batch size 400 tablets. Foromeprazole Mg-salt pellet production (core material, separating layer,enteric coating layer and over-coating layer, see WO 97/25066, p. 22-23under respective headings), see WO 97/25066, first two paragraphs, allof which is hereby incorporated by reference. Tablets Prepared pelletscomprising omeprazole Mg-salt 31.3 g Microcrystalline cellulose 300.0 g Cimetidine hydrochloride 40.0 g Potato starch 50.0 g Water 200.0 g  PVPcrosslinked 38.0 g Sodium stearyl fumarate  4.6 g

[0071] A small amount of the potato starch is dissolved in purified hotwater to form the granulation liquid. Cimetidine hydrochloride, the restof potato starch and microcrystalline cellulose are dry mixed. Thegranulation liquid is added to the dry mixture and the mass is wetmixed. The wet mass is dried in an oven at 50° C. The preparedgranulation is milled through sieve 1 mm in an oscillating millequipment. The enteric coating layered pellets with an over-coatinglayer, the prepared H2 receptor antagonist granules, crosslinkedpolyvinylpyrrolidone and sodium stearyl fumarate are mixed andcompressed into tablets using a tableting machine equipped with ovalpunches. The amount of omeprazole in each tablet is approx. 10 mg andthe amount of cimetidine hydrochloride is approx. 100 mg.

[0072] By a slight modification this multiple unit tablet form can bemade to comprise an antacid agent (instead of microcrystallinecellulose, 300 mg: microcrystalline cellulose, 100 g; calcium carbonate,100 mg; magnesium oxide, 100 mg; all other constituents, except water,in the amounts given above).

EXAMPLE 2

[0073] Three-layered tableted dosage form. The tablet comprises the acidsusceptible proton pump inhibitor omeprazole, a separating layer and acore layer comprising cimetidine hydrochloride. Batch size 1000 tablets.First tablet layer Cimetidine hydrochloride 200.0 g  Microcrystallinecellulose 250.0 g  PVP crosslinked 13.0 g Sodium stearyl fumarate  3.8 gSeparating layer Microcrystalline cellulose 80.0 g Second tablet layerEnteric coating layered pellets comprising 78.3 g omeprazole magnesiumsalt (same as in EXAMPLE 1) Microcrystalline cellulose 174.0 g  PVPcrosslinked 26.0 g Sodium stearyl fumarate  1.4 g

[0074] The constituents of the first tablet layer are dry mixed andprecompressed as a first layer in a tableting machine equipped with ovalpunches. Microcrystalline cellulose is filled on the top of the firstlayer to form a separating layer to the next layer. The constituents ofthe second tablet layer are dry mixed and filled on top of theseparating layer. The three layers are compressed into a three layertablet which may be coated by a tablet coating layer. The amount ofomeprazole is approx. 10 mg and that of cimetidine hydrochloride approx.200 mg per tablet.

EXAMPLE 3

[0075] Capsule dosage form. No. 1 hard gelatin capsules (16) (FIG. 5;volume 0.48 ml) were filled with enteric coated omeprazole pellets (15)containing 20 mg omeprazole recovered from commercially availableomeprazole (Losec®) capsules and a dry mixture 14 of commerciallyavailable famotidine 20 mg for injection (Pepcidin®; containing 20 mgfamotidine hydrochloride, 8 mg aspartic acid and 40 mg mannitol), andclosed.

EXAMPLE 4

[0076] Divided powder/pellet formulation. Enteric pellets containing 15mg lansoprazole recovered from commercially available capsules (Lanzo®,enterocapsules) and the famotidine preparation for injection of EXAMPLE4 were dry mixed with citric acid. Single dose portions thereofcontaining 10 mg each of lansoprazole and famotidine hydrochloride and200 mg powderous citric acid were dry packed in plastic laminate. Thecomposition is intended to be poured into 20 ml of water, stirred for ashort time, and swallowed.

EXAMPLE 5

[0077] Multiple unit capsule dosage form. The tabled comprises magnesiumomeprazole and famotidine hydrochloride. For enteric coating layer andover-coating layer, see WO 97/25066, page 22-23 under respectiveheadings, the information under which is hereby incorporated byreference.

[0078] Magnesium omeprazole is mixed with microcrystalline cellulosespheres to an ordered mixture. The ordered mixture is coated with anenteric coating layer consisting of methacrylic acid copolymer, mono-and diglycerides, triethyl citrate and polysorbate in a fluid bedapparatus. The enteric coated ordered mixture is then over-coated with awater suspension containing famotidine hydrochloride,hydroxypropylmethyl cellulose and magnesium stearate in a fluid bedapparatus. The enteric coated ordered mixture with an over-coating layerwas filled in hard gelatin capsules. The amount of omeprazole is approx.10 mg and that of famotidine hydrochloride approx. 20 mg per capsule.

EXAMPLE 7

[0079] Multiple unit tableted dosage form comprising magnesiumomeprazole and cimetidine hydrochloride. Magnesium omeprazole is mixedwith microcrystalline cellulose spheres to an ordered mixture which iscoated with an enteric coating layer as described in EXAMPLE 6.Cimetidine hydrochloride is granulated as described in EXAMPLE 1. Theenteric coated ordered mixture comprising magnesium omeprazole, thecimetidine granules and excipients are dry mixed and compressed intotablets. The amount of omeprazole in each tablet is approx. 10 mg andthat of cimetidine is approx. 100 mg.

EXAMPLE 8

[0080] Inhibition of gastric acid secretion. A healthy subject (male, 31years of age, having fasted for 10 hours) was provided with a doublelumen nasogastric tube through one nasal passage and with amicroelectrode for pH registration through the second nasal passage. Atwo point calibration of the electrode was performed before and aftereach 24 h recording, using standard buffers of pH 7.0 and 1.7. Theelectrode was placed 10 cm below the lower esophagal sphincter duringthe pH recording and the position marked on the electrode lead to ensureproper positioning during consecutive recordings. A commerciallyavailable omeprazole (Losec®) capsule containing 20 mg omeprazole wascarefully opened and the contents (pellets) placed in a plastic syringewhich had been put into communication with one of the lumina of thenasogastric tube. The syringe was filled with 20 ml tap water and thepellets injected through the nasogastric tube immediately thereafter.The syringe was flushed with 20 ml water. The gastric pH trace recordedby the microelectrode during a period of more than four hours isillustrated in FIG. 7. In a second experiment the syringe was filledwith the same amount of omeprazole micropellets and famotidine 20 mg forinjection (Pepcidin®; containing 20 mg famotidine, 8 mg aspartic acidand 40 mg mannitol), the procedure of injection and measurement beingthe same as with omeprazole. The gastric pH trace for the combination isillustrated in FIG. 8. The experiments demonstrate that a reduction ofpH to about 6 is obtained with the omeprazole/famotidine within about 2hours and maintained until the end of recording (4 hours from injection)whereas with omeprazole alone no increase in pH can be noted after 4hours from injection.

1. An oral pharmaceutical dosage form comprising pharmacologicallyeffective amounts of an acid susceptible proton pump inhibitor or a saltthereof and an H2 receptor antagonist or a salt thereof, and apharmaceutically acceptable carrier.
 2. The dosage form of claim 1,wherein the acid susceptible proton pump inhibitor is selected fromlanzoprazole, omeprazole, pantoprazole, rabeprazole, pariprazole,leminoprazole, their pharmaceutically acceptable salts, enantiomers andsalts of enantiomers.
 3. The dosage form of claim 1, comprising from 1mg to 100 mg per single dose of an acid susceptible proton pumpinhibitor or a salt thereof.
 4. The dosage form of any of claims 1-3,wherein the acid susceptible proton pump inhibitor or a salt thereof isseparated from the H2 receptor antagonist by an enteric coating.
 5. Thedosage form of claim 1, wherein the H2 receptor antagonist is selectedfrom cimetidine, ranitidine, nizatidine and famotidine, theirpharmaceutically acceptable salts, isomers and salts of isomers.
 6. Thedosage form of claim 1, comprising from 1 mg to 800 mg of H2 receptorantagonist or salt thereof.
 7. The dosage form of claim 1, wherein saidpharmacologically effective amounts are amounts capable to raise gastricpH to above 4 within two hours after administration and to keep it above4 for at least 4 hours.
 8. The dosage form of claim 7, wherein saidamounts are capable to keep gastric pH above 4 for at least 8 hours. 9.The dosage form of claim 1, wherein said pharmacologically effectiveamounts are amounts capable to raise gastric pH to above 3 within 2hours from administration and to keep it above 3 for at least 4 hours.10. The dosage form of claim 9, wherein said amounts are amounts capableto keep gastric pH above 3 for at least 8 hours.
 11. The dosage form ofany of claims 1-10, comprising from 100 mg to 1000 mg of antacid agentand/or alginate.
 12. The dosage form of claim 11, wherein the antacidagent comprises one or several of aluminum hydroxide, calcium carbonate,magnesium carbonate, basic magnesium carbonate, magnesium hydroxide,magnesium oxide, sodium hydrogen carbonate.
 13. The dosage form of anyof claims 1-12, wherein said acid susceptible proton pump inhibitor or asalt thereof is protected by an enteric coating layer and, optionally, alayer separating it from the enteric coating.
 14. The dosage form of anyof claims 1-13, comprising two concentric layers optionally separated byone or more separating layer(s), one layer comprising said acidsusceptible proton pump inhibitor or salt thereof, the other layercomprising said H2 receptor antagonist or salt thereof.
 15. The dosageform of claim 14, wherein the inner layer comprises the acid susceptibleproton pump inhibitor or salt thereof and the outer layer comprises theH2 receptor antagonist or salt thereof.
 16. The dosage form of claims14, wherein the outer layer comprises the acid susceptible proton pumpinhibitor or salt thereof and the inner layer comprises the H2 receptorantagonist or salt thereof.
 17. The dosage form of claim 16, wherein theinner layer comprises a disintegrant.
 18. A capsule according to any ofclaims 1-13.
 19. A divided powder/pellet formulation according to any ofclaims 1-13.
 20. A tablet according to any of claims 1-17.
 21. Thetablet of claim 20, divisible.
 22. The tablet of claim 20, dispersiblein water.
 23. The tablet of claim 22, comprising a disintegrant.
 24. Amethod for the manufacture of an oral tableted dosage form comprisingamounts of an acid susceptible proton pump inhibitor or salt thereof andan H2 receptor antagonist or salt thereof pharmacologically effective intreating a condition related to dyspepsia, the method comprising forminga first layer comprising said acid susceptible proton pump inhibitor orsalt thereof, an enteric coat surrounding said first layer, and a secondlayer comprising said H2 receptor antagonist or salt thereof surroundingsaid first layer and said enteric coat.
 25. A method for the manufactureof an oral dosage form comprising amounts of an acid susceptible protonpump inhibitor or salt thereof and an H2 receptor antagonist or saltthereof pharmacologically effective in treating a condition related todyspepsia, the method comprising forming pellets comprising said acidsusceptible proton pump inhibitor or salt thereof, covering said pelletswith enteric coat, and mixing said pellets covered with said entericcoat with a carrier comprising said H2 receptor antagonist or saltthereof.
 26. The method of claim 25, wherein said carrier comprises adisintegrant.
 27. The method of claim 25 or 26, comprising forming atablet of said mixture.
 28. The method of claim 25, comprising filling acapsule capable of disintegrating in gastrointestinal fluids to releaseits contents with said mixture.
 29. A method for the manufacture of anoral dosage form comprising amounts of an acid susceptible proton pumpinhibitor or salt thereof and an H2 receptor antagonist or salt thereofpharmacologically effective in treating a condition related todyspepsia, the method comprising forming a layer comprising an acidsusceptible proton pump inhibitor or salt thereof and an H2 receptorantagonist or salt thereof, and covering said layer with an entericcoat.
 30. A method for the manufacture of an oral dosage form comprisingamounts of an acid susceptible proton pump inhibitor or salt thereof andan H2 receptor antagonist or salt thereof pharmacologically effective intreating a condition related to dyspepsia, the method comprising formingmixture comprising an acid susceptible proton pump inhibitor or saltthereof and an H2 receptor antagonist or salt thereof, filling saidmixture in a capsule capable of disintegrating in gastrointestinalfluids to release its contents, and covering said capsule with anenteric coat.
 31. The method of any of claims 24-30, wherein said acidsusceptible proton pump inhibitor is selected from lansoprazole,omeprazole, pantoprazole, rabeprazole, pariprazole, leminoprazole, theirpharmaceutically acceptable salts, enantiomers and salts of enantiomers.32. The method of any of claims 24-30, wherein said H2 receptorantagonist is selected from are cimetidine, ranitidine, nizatidine andfamotidine, their pharmaceutically acceptable salts, isomers and saltsof isomers.
 33. Use of the dosage form of any of claims 1-23 for themanufacture of a medicament for the treatment of a disorder associatedwith gastric acid secretion.
 34. Use of the dosage form of any of claims1-23 in association with one or more antibiotic agent(s) for theeradication of Helicobacter pylori.
 35. A method of treating disordersassociated with dyspepsia, comprising the administration of the dosageform of any of claims 1-23 or the concomitant administration of twoseparate oral dosage forms, one comprising a pharmacologically effectiveamount of an acid susceptible proton pump inhibitor or salt thereof, theother comprising a pharmacologically effective amount of an H2 receptorantagonist or salt thereof.
 36. A method of treating an infection byHelicobacter pylori, comprising the administration of the dosage form ofany of claims 1-23 or the concomitant administration of two separateoral dosage forms, one comprising a pharmacologically effective amountof an acid susceptible proton inhibitor or salt thereof, the othercomprising a pharmacologically effective amount of an H2 receptorantagonist or salt thereof, in association with the administration ofone or more antibiotic agent(s) effective against H. pylori.
 37. Themethod of claim 35 or 36, comprising a dose regimen capable ofmaintaining gastric pH above 4 for at least 95% of the time periodstarting at 2 hours from the administration of the first dose andextending until 6 hours from the administration of the last dose. 38.The method of claim 37, wherein said time period is one week or more.39. The method of claim 37, wherein said time period is two weeks ormore.
 40. The method of claim 37, wherein said time period is four weeksor more.
 41. The method of claim 35 or 36, comprising a dose regimencapable of maintaining gastric pH above 3 for at least 95% of the timeperiod starting at 2 hours from the administration of the first dose andextending until 6 hours from the administration of the last dose, inparticular for four weeks or more.